(1) Field of the invention
This invention relates to the uses of fenclofenac (2-(2,4-dichloro-phenoxyphenylacetic) acid as an immuno-suppressant drug.
(2) Description of the prior art
A non-steroidal anti-inflammatory drug (NSAID) relieves the symptoms of the disease for which it is prescribed. All NSAIDs inhibit the enzyme cyclooxygenase and therefore decrease the production of prostaglandins and thromboxane A2. This effect is thought to be responsible for the alleviation of the symptoms due to inflammation, especially in diseases such as rheumatoid arthritis for which they are principally prescribed. Fenclofenac, which is described and claimed in the specification of British Patent No. 1308327, is an example of an NSAID which was marketed for many years for the treatment of rheumatoid arthritis.
Some NSAIDs also inhibit lipoxygenases and may reduce local inflammation and polymorphonuclear leucocyte activation by inhibition of leukotriene B4.
Prostaglandin inhibition is also thought to be responsible for the adverse effects of NSAIDs on the gastro-intestinal tract--an unwanted side effect of these drugs. However these side effects are easier to manage than those due to steroid therapy and to other immunosuppressive drugs which are needed to treat severe disease and to modify the disease process.
In rheumatoid arthritis the synovial membranes of the joints are involved in an intense cellular infiltration. The infiltrating cells are lymphocytes, plasma cells and macrophage-like cells. Polymorphonuclear leucocytes (neutrophils) are scanty o absent in the membrane but plentiful in the synovial fluid in the joint cavity. 80% of the lymphocytes present in the rheumatoid synovial membrane are T cells and 20% are B cells. Of the T cells present the ratio of T-helper to T-suppressor cells is in the order of 10:1 compared with 2:1 in normal lymph nodes or blood. The role of synovial lymphocytes in the pathogenesis of rheumatoid arthritis has been established by the thoracic duct drainage studies of Paulus et al., which showed improvement of the disease following removal of thoracic duct lymphocytes and, in selected cases, flare-up of the disease on reinfusion. Studies using lymphopheresis have confirmed the improvement in the disease of rheumatoid arthritis after removal of lymphocytes from the peripheral blood.
There is some evidence from experimental animal studies that fenclofenac is more effective than other non-steroidal anti-inflammatory drugs in inhibiting chronic immunologically mediated inflammation than in alleviating acute irritant-induced inflammation [Atkinson, D. C. and Leach, E. C. Agents and Actions, 6, (5), 657-666 (1976)]. In a preliminary study on the immuno-inflammatory pharmacology of fenclofenac Philips, N. C. [Fenclofenac in Arthritis An International Symposium (eds. Swain, M. C. and Goldberg, A. A. J.) Royal Society of Medicine, pp. 83-88 (1980)] shows that fencloenac is not active during the initial humoral phase of a delayed type hypersensitivity reaction in mice but is active during the later phase. Although the other drugs tested, such as diclofeac and indomethacin, had an even greater effect during the later stages, and an effect greater than that of fenclofenac, and although none of the compounds tested (with the exception of cyclophosphamide which was included as a known immunomodulator) was found to have any significant effect on the percentage of T- and B-lymphocytes, Philips nevertheless draws the conclusion that fenclofenac may be acting specifically at a more fundamental level in inhibiting immunologically mediated inflammation than a number of other non-steroidal anti-inflammatory drugs.
In an abstract [Rev. Bras. Reumat 22(3), 139 (1982)] of a paper to be given at the Brazilian Congress of Rheumatology, Recife, in July 1982, Matheus P. C. et al. followed a previous suggestion that fenclofenac has the capacity to induce remissions in the natural evolution of rheumatoid arthritis by observing the effect of fenclofenac on the function of neutrophils, monocytes and lymphocytes.
In view of the incompleteness of the report, in particular with respect to dose responses, and to a definition of "physiological concentrations of fenclofenac", it is difficult to appreciate the statistical significance of the low blastic transformation counts; the two earlier papers to which reference is made for a description of the techniques employed lack such a description for the blastic transformation of lymphocytes. It is consequentially difficult to evaluate the authors' assertion that fenclofenac proved to be a powerful inhibitor of the function of lymphocytes. The author's eventual conclusion from their work is limited to the suggestion that fenclofenac may be of real value in the treatment of long term rheumatoid arthritis.